PDEs are enzymes which hydrolyze intracellular cyclic AMP (cAMP) and intracellular cyclic GMP (cGMP) and widely distributed in vivo in various tissues and organs. Up to now, it has been known that PDEs are classified into 7 isoenzyme families, i.e., type I to VII PDEs (PDE I to VII), according to their properties. Among them, PDE IV is known to be an enzyme which is predominantly present in airway smooth muscle cells and a wide variety of inflammatory cells, i.e., neutrophils, eosinophils, lymphocytes, etc. and selectively breaks down cAMP. In addition, it has been known that an elevation of cAMP levels in airway smooth muscle cells leads to relaxation of the airway smooth muscles. An increase of cAMP levels in inflammatory cells has also been known to suppress an activation of inflammatory cells, including, for example, a release of cytotoxic proteins from eosinophils, etc.
Therefore, if PDE IV predominantly located in airway smooth muscle cells and inflammatory cells is inhibited by inhibitors selective for said isozyme form, an elevation of cAMP levels would be induced in such cells. As a result, it would be expected to elicit bronchodilator actions via relaxing airway smooth muscles and anti-inflammatory actions through suppressing inflammatory cell activation. Such selective inhibitors of PDE IV would be expected to become excellent anti-asthmatic agents and therapeutic agents for chronic obstructive pulmonary disease (COPD).
Up to now, it has been known that a xanthine derivative theophylline, a catechol derivative rolipram, and the like, are inhibitors of PDE IV. Theophylline inhibits PDE in various tissues due to its non-selectivity for individual isozymes, thereby exerting not only a bronchodilator activity to be targeted but also extra actions on heart, CNS, etc. Although rolipram is observed to be selective for PDE IV, it is easily transferred into the CNS due to its property of being absorbed. Therefore, rolipram has a drawback that it has adverse central side-effects effects such as an emetic action.
Over the past decade, many pharmaceutical companies have focused on the inhibition of PDE IV for the treatment of asthma. The biological studies on the PDE IV isozyme and the structure-activity relationship of said inhibitors have recently been reviewed in the literature. In such processes, it has been pointed out that in general the therapeutic utility of selective PDE IV inhibitors, such as the prototypical agent rolipram, have been hampered by nausea and emesis limiting their therapeutic potential (J. Med. Chem., 41: 2268 to 2277 (1998)).
Under these circumstances, in order to find out pharmaceutical drugs having an excellent anti-asthmatic efficacy via minimizing undesirable side-effects in tissues and organs other than bronchial smooth muscles and inflammatory cells, various PDE IV inhibitors have been screened and examined.
For instance, with an aim at inhibitors with improved selectivity for PDE IV, various compounds including diazepinoindoles (JP, A, 10-507447 (1998)), tri-substituted phenyl derivatives (JP, A, 10-504530 (1998), JP, A, 10-503174 (1998), JP, A, 10-503173 (1998), etc.), naphthalene derivatives (JP, A, 10-226647 (1998)), etc., have been proposed.
Besides these, for the purpose of developing not only anti-asthmatics but also pharmaceutical agents for preventing and treating a wide range for diseases, PDE IV-inhibitory compounds having a naphthyridine ring have been proposed in JP, A, 7-10875 (1995); WO 96/6843, A1; JP, A, 11-106385 (1999); etc.
Such compound groups are, however, unsatisfactory in view of solving the aforementioned problems. There is still a demand for anti-asthmatics which exert more selective PDE IV-inhibiting actions and have advantageous properties from aspects regarding both of efficacy and safety.